Lung cancer is one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent subtype. Gemcitabine is a primary clinical option for the treatment of NSCLC. Nevertheless, it encounters challenges including drug resistance and severe adverse effects. High expression of regulator of G protein signaling 2 (RGS2) is associated with poor prognosis in NSCLC. Usenamine A (UD32-3), a natural compound derived from lichen usnea longissimi, exerts anti-tumor activities in certain types of cancer cells, however, its underlying molecular mechanisms in NSCLC are largely unknown. In this study, we demonstrated for the first time that UD32-3 exerts anti-NSCLC activity by targeting RGS2, thereby suppressing Notch1 to induce autophagy and promoting reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress. Suppression of RGS2 inhibited cell growth by inducing ROS-mediated ER stress and Notch1-mediated autophagy in NSCLC, whereas its overexpression had the opposite effects. Additionally, combined therapy with UD32-3 and gemcitabine exerted synergistic anti-NSCLC activity. Our findings suggest that RGS2 is a promising therapeutic target for the treatment of NSCLC, and combined therapy with UD32-3 and gemcitabine might be an alternative therapeutic strategy for certain NSCLC patients.
